Sustained and potent analgesia with negligible side effects enabled by adaptive individualized granular stimulation in rat brainstem.

Objectives.To clarify if an adaptive current stimulation protocol, in which current amplitude is modulated during continuous stimulation, provides better efficacy than constant current stimulation protocol with respect to analgesia caused by individualized stimulation in rat periaqueductal gray matter (PAG) /dorsal raphe nuclei (DRN).Approach.Ultrathin microelectrodes adapted for recording (n= 6) and stimulation (n= 16) were implanted in rat primary somatosensory cortex and PAG/DRN, respectively. In each animal included (n= 12), a subset of PAG/DRN microelectrodes (n= 1-3 per animal) was selected that on simultaneous stimulation blocked nociceptive withdrawal reflexes in awake unrestrained animals without noticeable side effects. Analgesic effects were subsequently assessed from both nociceptive withdrawal reflexes and intracortical pain-related responses on CO2laser hind paw stimulation. The analgesic effects of adaptive current PAG/DRN stimulation comprising incremental increases of 5µA/microelectrode (initial median current 30µA/microelectrode) when effects declined were compared to the effects of constant current stimulation. Behavioral effects and brain state related changes were analyzed using quantitative movement analysis and electrocorticography (recorded on top of the dura mater), respectively. Tissue reactions and probe placement in PAG/DRN were assessed with immunohistochemistry.Main results.Powerful and sustained (4 h) analgesia was achieved with the adaptive current protocol within a rather wide area of PAG/DRN. Analgesic after-effects were seen for up to 30 min. Behavioral and brain state related side effects were minimal. Moreover, 6 weeks after implantation, there were no traces of bleedings, only small glial reactions and small but not statistically significant loss of neurons nearby indicating that the microelectrode stimulation employed is biocompatible.Significance.The results indicate that sustained and powerful analgesia with minimal side effects can be achieved by granular and individualized stimulation in PAG/DRN using an adaptive current stimulation protocol. This microelectrode technology and stimulation paradigm thus has the potential of providing a highly efficient and safe pain therapy.

3D microelectrode cluster and stimulation paradigm yield powerful analgesia without noticeable adverse effects.

The lack of satisfactory treatment for persistent pain profoundly impairs the quality of life for many patients. Stimulation of brainstem pain control systems can trigger powerful analgesia, but their complex network organization frequently prevents separation of analgesia from side effects. To overcome this long-standing challenge, we developed a biocompatible gelatin-embedded cluster of ultrathin microelectrodes that enables fine-tuned, high-definition three-dimensional stimulation in periaqueductal gray/dorsal raphe nucleus in awake rats. Analgesia was assessed from both motor reactions and intracortical signals, corresponding to pain-related signals in humans. We could select an individual-specific subset of microelectrodes in each animal that reliably provided strong pain inhibition during normal and hyperalgesia conditions, without noticeable behavioral side effects. Gait, spontaneous cortical activity at rest, and cortical tactile responses were minimally affected, indicating a highly selective action. In conclusion, our developed biocompatible microelectrode cluster and stimulation paradigm reliably enabled powerful, fine-tuned, and selective analgesia without noticeable side effects.

Local delivery of minocycline-loaded PLGA nanoparticles from gelatin-coated neural implants attenuates acute brain tissue responses in mice.

BACKGROUND: Neural interfaces often elicit inflammatory responses and neuronal loss in the surrounding tissue which adversely affect the function and longevity of the implanted device. Minocycline, an anti-inflammatory pharmaceutics with neuroprotective properties, may be used for reducing the acute brain tissue responses after implantation. However, conventional administration routes require high doses which can cause adverse systemic side effects. Therefore, the aim of this study was to develop and evaluate a new drug-delivery-system for local and sustained administration of minocycline in the brain. METHODS: Stainless steel needles insulated with Parylene-C were dip-coated with non-crosslinked gelatin and minocycline-loaded PLGA nanoparticles (MC-NPs) were incorporated into the gelatin-coatings by an absorption method and subsequently trapped by drying the gelatin. Parylene-C insulated needles coated only with gelatin were used as controls. The expression of markers for activated microglia (CD68), all microglia (CX3CR1-GFP), reactive astrocytes (GFAP), neurons (NeuN) and all cell nuclei (DAPI) surrounding the implantation sites were quantified at 3 and 7 days after implantation in mice. RESULTS: MC-NPs were successfully incorporated into gelatin-coatings of neural implants by an absorption method suitable for thermosensitive drug-loads. Immunohistochemical analysis of the in vivo brain tissue responses, showed that MC-NPs significantly attenuate the activation of microglial cells without effecting the overall population of microglial cells around the implantation sites. A delayed but significant reduction of the astrocytic response was also found in comparison to control implants. No effect on neurons or total cell count was found which may suggest that the MC-NPs are non-toxic to the central nervous system. CONCLUSIONS: A novel drug-nanoparticle-delivery-system was developed for neural interfaces and thermosensitive drug-loads. The local delivery of MC-NPs was shown to attenuate the acute brain tissue responses nearby an implant and therefore may be useful for improving biocompatibility of implanted neuro-electronic interfaces. The developed drug-delivery-system may potentially also be used for other pharmaceutics to provide highly localized and therefore more specific effects as compared to systemic administration.